Dylan M. Nielson

Restoring cortical control of functional movement in a human with quadriplegia

Millions of people worldwide suffer from diseases that lead to paralysis through disruption of signal pathways between the brain and the muscles. Neuroprosthetic devices are designed to restore lost function and could be used to form an electronic ‘neural bypass’ to circumvent disconnected pathways in the nervous system. It has previously been shown that intracortically recorded signals can be decoded to extract information related to motion, allowing non-human primates and paralysed humans to control computers and robotic arms through imagined movements. In non-human primates, these types of signal have also been used to drive activation of chemically paralysed arm muscles. Here we show that intracortically recorded signals can be linked in real-time to muscle activation to restore movement in a paralysed human. We used a chronically implanted intracortical microelectrode array to record multiunit activity from the motor cortex in a study participant with quadriplegia from cervical spinal cord injury. We applied machine-learning algorithms to decode the neuronal activity and control activation of the participant’s forearm muscles through a custom-built high-resolution neuromuscular electrical stimulation system. The system provided isolated finger movements and the participant achieved continuous cortical control of six different wrist and hand motions. Furthermore, he was able to use the system to complete functional tasks relevant to daily living. Clinical assessment showed that, when using the system, his motor impairment improved from the fifth to the sixth cervical (C5–C6) to the seventh cervical to first thoracic (C7–T1) level unilaterally, conferring on him the critical abilities to grasp, manipulate, and release objects. This is the first demonstration to our knowledge of successful control of muscle activation using intracortically recorded signals in a paralysed human. These results have significant implications in advancing neuroprosthetic technology for people worldwide living with the effects of paralysis.

Human hippocampus represents space and time during retrieval of real-world memories

Significance The rodent hippocampus contains neurons that code for space on the scale of meters, a discovery that was recently awarded a Nobel Prize. However, it remains unclear whether humans harness similar representations for memory at the scale of their lives. Our results reveal that the human hippocampus represents the spatial and temporal location of memories for real-life events at scales of up to 30 km and a month of time. They further suggest that real-world representations of space and time are more intimately entwined in the hippocampus than previously thought, validating the relevance of decades of rodent studies for human memory and providing a potential mechanism for how we weave the episodic memories of our lives. Memory stretches over a lifetime. In controlled laboratory settings, the hippocampus and other medial temporal lobe brain structures have been shown to represent space and time on the scale of meters and seconds. It remains unclear whether the hippocampus also represents space and time over the longer scales necessary for human episodic memory. We recorded neural activity while participants relived their own experiences, cued by photographs taken with a custom lifelogging device. We found that the left anterior hippocampus represents space and time for a month of remembered events occurring over distances of up to 30 km. Although previous studies have identified similar drifts in representational similarity across space or time over the relatively brief time scales (seconds to minutes) that characterize individual episodic memories, our results provide compelling evidence that a similar pattern of spatiotemporal organization also exists for organizing distinct memories that are distant in space and time. These results further support the emerging view that the anterior, as opposed to posterior, hippocampus integrates distinct experiences, thereby providing a scaffold for encoding and retrieval of autobiographical memories on the scale of our lives.

A Magnetization Transfer Imaging Study of Corpus Callosum Myelination in Young Children with Autism

BACKGROUND Several lines of evidence suggest that autism may be associated with abnormalities in white matter development. However, inconsistencies remain in the literature regarding the nature and extent of these abnormalities, partly because of the limited types of measurements that have been used. Here, we used magnetization transfer imaging to provide insight into the myelination of the corpus callosum in children with autism. METHODS Magnetization transfer imaging scans were obtained in 101 children with autism and 35 typically developing children who did not significantly differ with regard to gender or age. The midsagittal area of the corpus callosum was manually traced and the magnetization transfer ratio (MTR) was calculated for each voxel within the corpus callosum. Mean MTR and height and location of the MTR histogram peak were analyzed. RESULTS Mean MTR and MTR histogram peak height and location were significantly higher in children with autism than in typically developing children, suggesting abnormal myelination of the corpus callosum in autism. CONCLUSIONS The differences in callosal myelination suggested by these results may reflect an alteration in the normally well-regulated process of myelination of the brain, with broad implications for neuropathology, diagnosis, and treatment of autism.

Preliminary Guidelines for Safe and Effective Use of Repetitive Transcranial Magnetic Stimulation in Moderate to Severe Traumatic Brain Injury

Transcranial magnetic stimulation has generated extensive interest within the traumatic brain injury (TBI) rehabilitation community, but little work has been done with repetitive protocols, which can produce prolonged changes in behavior. This is partly because of concerns about the safety of repetitive transcranial magnetic stimulation (rTMS) in subjects with TBI, particularly the risk of seizures. These risks can be minimized by careful selection of the rTMS protocol and exclusion criteria. In this article, we identify guidelines for safe use of rTMS in subjects with TBI based on a review of the literature and illustrate their application with a case study. Our subject is a 48-year-old man who sustained a severe TBI 5 years prior to beginning rTMS for the treatment of post-TBI depression. After a 4-week baseline period, we administered daily sessions of low-frequency stimulation to the right dorsolateral prefrontal cortex for 6 weeks. After stimulation, we performed monthly assessments for 3 months. The Hamilton Depression Rating Scale (HAMD) was our primary outcome measure. The stimulation was well tolerated and the patient reported no side effects. After 6 weeks of stimulation, the patients depression was slightly improved, and these improvements continued through follow-up. At the end of follow-up, the patients HAMD score was 49% of the average baseline score.

Improved Function After Deep Brain Stimulation for Chronic, Severe Traumatic Brain Injury.

BACKGROUND Severe traumatic brain injury (TBI) damages the frontal lobes and connecting networks, which impairs executive functions, including the ability to self-regulate. Despite significant disabling effects, there are few treatment options in the chronic phase after injury. OBJECTIVE To investigate the safety and potential effectiveness of deep brain stimulation (DBS) for individuals with chronic, disabling TBI and problems of behavioral and emotional self-regulation. METHODS This study was an open-label, prospective design with serial assessments of behavioral outcomes and positron emission tomography 2 years after DBS implantation. Four participants 6 to 21 years after severe TBIs from automobile crashes were included. Although alert and volitional, all experienced significant executive impairments, including either impulsivity or reduced initiation. DBS implants were placed bilaterally in the nucleus accumbens and anterior limb of the internal capsule to modulate the prefrontal cortex. RESULTS The procedure was safe, and all participants had improved functional outcomes. Two years after implantation, 3 met a priori criteria for improvement on the Mayo-Portland Adaptability Inventory-4. Improvement was due largely to better emotional adjustment, although 1 participant showed marked increases in multiple domains. Significant improvement in a composite score of functional capacity indicated improved independence in self-care and activities of daily living. The pattern of change in cognition corresponded with changes in activation of the prefrontal cortex observed in serial scanning. CONCLUSION This first study of DBS to this target for severe TBI supports its safety and suggests potential effectiveness to improve function years after injury. The primary impact was on behavioral and emotional adjustment, which in turn improved functional independence. ABBREVIATIONS DBS, deep brain stimulationIC, internal capsuleMPAI-4, Mayo-Portland Adaptability Inventory-4NAcc, nucleus accumbensTBI, traumatic brain injury.

Spinal Cord Stimulation (SCS) and Functional Magnetic Resonance Imaging (fMRI): Modulation of Cortical Connectivity With Therapeutic SCS

The neurophysiological basis of pain relief due to spinal cord stimulation (SCS) and the related cortical processing of sensory information are not completely understood. The aim of this study was to use resting state functional magnetic resonance imaging (rs‐fMRI) to detect changes in cortical networks and cortical processing related to the stimulator‐induced pain relief.

Deep Brain Stimulation of Frontal Lobe Networks to Treat Alzheimer’s Disease

The study objective was to evaluate the safety and efficacy of deep brain stimulation (DBS) at the ventral capsule/ventral striatum (VC/VS) region to specifically modulate frontal lobe behavioral and cognitive networks as a novel treatment approach for Alzheimers disease (AD) patients. This is a non-randomized phase I prospective open label interventional trial of three subjects with matched comparison groups. AD participants given DBS for at least 18 months at the VC/VS target were compared on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), our primary outcome clinical measure, to matched groups without DBS from the AD Neuroimaging Initiative (ADNI) cohort. Serial 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) images of AD participants were also compared longitudinally over time. Three AD DBS participants were matched to subjects from the ADNI cohort. All participants tolerated DBS well without significant adverse events. All three AD DBS participants had less performance decline and two of them meaningfully less decline over time on our primary outcome measure, CDR-SB, relative to matched comparison groups from the ADNI using score trajectory slopes. Minimal changes or increased metabolism on FDG-PET were seen in frontal cortical regions after chronic DBS at the VC/VS target. The first use of DBS in AD at a frontal lobe behavior regulation target (VC/VS) was well-tolerated and revealed less performance decline in CDR-SB. Frontal network modulation to improve executive and behavioral deficits should be furthered studied in AD.

The experience of vivid autobiographical reminiscence is supported by subjective content representations in the precuneus

The human posteromedial cortex, which includes core regions of the default mode network (DMN), is thought to play an important role in episodic memory. However, the nature and functional role of representations in these brain regions remain unspecified. Nine participants (all female) wore smartphone devices to record episodes from their daily lives for multiple weeks, each night indicating the personally-salient attributes of each episode. Participants then relived their experiences in an fMRI scanner cued by images from their own lives. Representational Similarity Analysis revealed a broad network, including parts of the DMN, that represented personal semantics during autobiographical reminiscence. Within this network, activity in the right precuneus reflected more detailed representations of subjective contents during vivid relative to non-vivid, recollection. Our results suggest a more specific mechanism underlying the phenomenology of vivid autobiographical reminiscence, supported by rich subjective content representations in the precuneus, a hub of the DMN previously implicated in metacognitive evaluations during memory retrieval.